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Calcimimetic Agents: Review and Perspectives

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Calcimimetic Agents: Review and Perspectives View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 63, Supplement 85 (2003), pp. S91–S96 Calcimimetic agents: Review and perspectives PABLO UREN˜ A and JOA˜ O M. FRAZA˜ O Service de Ne´phrologie et Dialyse, Clinique de l’Orangerie, Aubervilliers, France; and Department of Nephrology, Hospital Sa˜o Joa˜o, Porto, Portugal School of Medicine, University of Porto, Portugal Calcimimetic agents: Review and perspectives. tal surgical parathyroidectomy every year as a result of Background. Recognition of the role of the extracellular treatment failure or severe clinical complications [4]. calcium-sensing receptor (CaR) in mineral metabolism has Parathyroid surgery is associated with major risks related greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in the extracel- to anesthesia, pre- and post-surgical complications, in- 2ϩ lular ionized calcium (ec(Ca )) regulates PTH, calcitonin secre- duction of permanent hypoparathyroidism, or recur- tion, urinary calcium excretion, and, ultimately, bone turnover. rence of the secondary hyperparathyroidism. The hypo- Methods. The cloning of the CaR and the discovery of muta- parathyroid state is associated with low bone remodeling, tions that make the receptor less or more sensitive to calcium have allowed a better understanding of several hereditary dis- adynamic bone disease, increased serum calcium and orders characterized by either hyperparathyroidism or hypo- phosphorus product, vascular calcifications, and the dev- parathyroidism. The CaR, able to amplify the sensitivity of the astating lesions of calciphylaxis [5–7]. Thus, the ideal CaR to Caϩϩ and suppress PTH levels with a resulting decrease ϩϩ treatment would be a drug that could efficiently, safely, in blood Ca , became an ideal target for the development of and cyclically suppress the secretion of parathyroid hor- compounds, the calcimimetics. Experience with the calcimi- metic R-568 in patients with primary and secondary hyperpara- mone (PTH) without interfering with the calcium and thyroidism and parathyroid carcinoma are summarized. phosphorus intestinal absorption. Results. The first clinical studies with the first-generation calcimimetic agents have demonstrated their efficacy in low- Parathyroid cell calcium-sensing receptor ering plasma intact PTH concentration in uremic patients with During the last 25 years, scientists have been interested secondary hyperparathyroidism. However, the low bioavail- ability of these first calcimimetics predicts a difficult clinical in demonstrating that the secretion of PTH is mainly utilization. The second-generation calcimimetic, AMG 073, regulated by a membrane receptor on the parathyroid having a better pharmacokinetic profile, appears to be effective cells which is capable of responding to small variations and safe for the treatment of secondary hyperparathyroidism, in the extracellular ionized calcium ( (Ca2ϩ)) concentra- suppressing PTH levels while simultaneously reducing serum ec phosphorus levels and the calcium x phosphorus product. tion. It was only in 1993 that Brown et al [8] cloned the Conclusion. The advantage of controlling PTH secretion parathyroid cell calcium-sensing receptor (CaR). This is without the complications related to hypercalcemia, hyper- a 121-kD protein with three main structural domains, a phosphatemia, and increased calcium x phosphorus product is long extracellular N-terminal domain, seven membrane- very promising. spanning helices, and a hydrophobic intracellular C-ter- minus characteristic of G-protein coupled receptors. The CaR belongs to the type III family of structurally unique More than a century after its identification, secondary G protein-coupled receptors, which includes other CaRs, hyperparathyroidism remains a problem in more than metabotropic glutamate receptors (mGluR1-8), putative one third of patients with chronic renal insufficiency pheromone receptors expressed in the rodent vomerona- [1–3]. Despite the use of new vitamin D analogs and new sal organ (V2Rs), three sweet taste receptors (T1R1-3), calcium-free, aluminum-free phosphate binders, many and GABAB receptors [9]. The parathyroid and kidney patients with secondary hyperparathyroidism are not CaRs are 1081 and 1079 amino acid long proteins, respec- controlled due to vitamin D–associated hypercalcemia tively. The CaR can be considered a low-affinity receptor, and hyperphosphatemia, or parathyroid gland resistance. 2ϩ responding to relatively high concentration of ec(Ca ), Three percent to 5% of patients require a total or subto- over one mmol/L. The limited selectivity of the receptor is responsible for its activation by numerous divalent or trivalent cations in addition to calcium, such as magne- Key words: calcium-sensing receptor, calcimimetics, secondary hyper- parathyroidism, hypocalcemia, parathyroid hormone, renal osteodys- sium, gadolinium, aluminum, and lanthanum, and by trophy, review. other polycationic compounds such as neomycin, sper- 2003 by the International Society of Nephrology mine, and numerous amino acids [10, 11]. The activation S-91 S-92 Uren˜a and Fraza˜o: Calcimimetic agents of the CaR by any one of these agonists results in the Table 1. Agonists and antagonists of the calcium receptors stimulation of the Gi protein, phospholipase C, inositide Agonists trisphosphate cascade, the mobilization of intracellular Type I calcimimetics Positive charges EC50 calcium, and the activation of protein kinase C (PKC). Inorganic cations Its activation also inhibits the adenylcyclase signaling Calcium 2 1.2 mmol Magnesium 2 5.2 mmol pathway and protein kinase A (PKA) [8, 12]. Modifica- Lanthanum 3 33 ␮m tions in these signal transduction pathways result in the Gadolinium 3 20 ␮m inhibition of PTH secretion. Aluminum 3 4 mmol Barium 2 — The physiologic relevance of the cloned CaR in de- Cadmium 2 — 2ϩ termining the level at which circulating ecCa is set has Nickel 2 — been established by the identification of several inherited Cobalt 2 — Iron 2 — diseases due to inactivation or activation mutations in Lead 2 0.1 mmol the parathyroid CaR gene, namely familial hypocalciuric Polyamines hypercalcemia, neonatal severe hyperparathyroidism, Spermine 3 150 ␮m Spermidine 4 2.0 mmol and familial hypercalciuric hypocalcemia [12–14]. Pentaethylenehexamine 6 500 ␮m Hexacyclin 6 21 ␮m Calcimimetic agents Aminosides Streptomycin 3 600 ␮m After discovery of the CaR there was interest in the Bekanamycin 5 200 ␮m development of compounds with the capacity of modu- Gentamycin 5 150 ␮m lating the function of the receptor, thus providing an- Neomycin 6 30 ␮m Polybasic amino acids and other tool for the medical treatment of both primary other peptides and secondary hyperparathyroidism (Table 1) [10, 15– Protamine 21 75 ␮m 17]. The first compounds were called “type I calcimimet- Polylysine (38 kD) 55 3 nmol 2ϩ Polyarginine (100 kD) 640 4 nmol ics” because they mimicked the effects of ecCa . The Type II calcimimetics second compounds were called “type II calcimimetics” NPS R-467 1 4.8 ␮m because they changed the structural conformation of the NPS S-467 1 70 ␮m NPS R-568 1 0.6 ␮m CaR and stereo-selectively increased its sensitivity to NPS S-568 1 9.8 ␮m 2ϩ ecCa . Type II calcimimetics lose their effect in the ab- AMG 073 — 2.8 ␮m 2ϩ KRN568 — (Cmax) 6.5 ng/mL sence of ecCa and do not really mimic the effect of 2ϩ Others ecCa ; therefore, naming them calcimimetics is probably Thimerosal (merthiolate) — — inappropriate and they should be called “positive allo- Antagonists steric modulators of CaR.” The third compounds have Calcilytics NPS 2143 — — been called “calcilytics” because they inhibit CaR func- tion and stimulate PTH secretion [10, 17]. It has been suggested by site-directed mutagenesis studies that the mode of action of the type II calcimimetics agents may cemia might be due to the abolition of PTH secretion reside in its binding to the seventh transmembrane do- main of the CaR [18]. Several calcimimetic agents have with a decrease in bone turnover, and not to the stimula- already been developed: first-generation compounds, in- tion of the renal CaR [19, 20]. cluding NPS R-567, NPS S-567, NPS R-568, NPS S-568, Six heterogeneous studies in uremic animals with sec- and KRN-568, and a second-generation compound, AMG ondary hyperparathyroidism have been published (Table 073. 2). In these studies, NPS R-568 at doses ranging from 1.5 to 15 mg/kg/day reduced the proliferation rate of Action of calcimimetic agents in vitro and in animals parathyroid cells by 50%, stopped the progression of The calcimimetic agents suppress the secretion of PTH parathyroid gland hyperplasia, and corrected the histo- in a dose-dependent manner in cultured parathyroid cells logic signs of high bone turnover [19, 21–25]. and in healthy animals. In animals, oral NPS R-568 pro- Clinical use of calcimimetic agents vokes a rapid dose-dependent (ED50, 1.1 Ϯ 0.7 mg/kg) decrease in serum PTH and calcium concentrations. At Calcimimetic agents have been tested in subjects with a dose of 3.3 mg/kg, the maximum effect on PTH levels normal renal function [26, 27]. In one study, 18 post- is reached 15 minutes after administration. At doses menopausal women were randomized into two groups; ranging from 10 to 100 mg/kg, hypocalcemia is almost one group received increasing doses of oral NPS R-568 immediate, lasting for more than 24 hours. Studies per- (10 to 400 mg/day), and the other group was treated with formed in rats submitted to bilateral nephrectomy and placebo. The levels of intact PTH decreased by 34% parathyroidectomy suggest that the striking hypocal- from baseline values 30 to 120 minutes after the dose of Uren˜a and Fraza˜o: Calcimimetic agents S-93 Table 2. Calcimimetics in animals with uremic secondary hyperparathyroidism Duration Reference Type of CRF Dose of calcimimetic of treatment Main results Wada et al [21] Nx. 5/6th 1.5–15 mg/kg/b.i.d. (gavage) 4 days 50% reduction in the proliferation rate of parathyroid cells Fox et al [19] Nx. 5/6th 5–10 mg/kg/q.i.d.
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